Pathology of Renal Artery Stenosis

Renal artery stenosis is the narrowing of both renal arteries or their branches That

might results in restriction of blood flow to the kidneys. That can cause hypertension by

initiating the release of the enzyme rennin from juxta glomrular cells of affected kidney.

The cross section of the lumen must be decreased by at least 60-70 % before the

occlusion becomes hemodynamically significant It is the most frequent cause of curable

hypertension (RVH) but it accounts for less 2% of all cases of hypertension (Berkow et

al., 1992).

RVH occurs when RAS produces a critical narrowing of the artery that supplies one of

the kidneys. Critical RAS is defined as at least 70% narrowing of the renal artery, based

on angiographic (blood vessel x-ray) evaluation.

When the blood flow through the kidneys decreases ,as incase of renal artery stenosis,the

juxtyaglomrular cells start to secrete rennin itself is an enzyme that splits the end of one

the plasma proteins, called angiotesinogen,to release angiotensin I ,two additional amio-

acids are split from angiotensin II This conversion occurs almost entirely in the small

vessels

Of the lung, catalyzed by an enzyme called converting enzyme. Angiotensin persists in

The blood for a minute or so but it is rapidly inactivated by number of blood and tissue

enzymes collectively known as angiotensinase

To angiotensin III which has some biological activity. Angiotensin II in the blood has

several effects that raises the blood pressure ,the main effect being vasoconstriction of the

both arterioles and to lesser extent the vein which causes an increase in the peripheral

resistance and the main circulatory filling pressure.Ngiotensin II also affects the body

fluid volume causing salt and water retention due to its direct effect on the kidneys and

by stimulating the secretion of aldosteron from the adrenal cortex .Angiotensin III main

effect is to stimulate aldosteron secretion ,causing salt and water retention which in turn

leads to an increase in the cardiac output ( Berkow et al .,1992)

Renal artery stenosis has several causes:

1- Atherosclerosis

2- Fibromuscular displasia

3- Dissecting aneurysms

4- Takaysu's Disease

5- Other rare causes such as Renovascular diseases ,Polyarteritis nodosa,

Neurofibromatosis ,emboli and traumatic thrombosis ( Robbins et al.,1994)

In most cases it is caused by build up of cholesterol and lipid on the lining of arteries

(atherosclerosis). This is the same disease that causes heart attack and angina when it

affects arteries of the heart. Occasionally other things are responsible:

( In renal artery stenosis, plaque builds up on the inner wall of the artery that supplies blood to the kidney.)

Risk Factors :

Risk factors associated with the development of atherosclerotic RAS include the following:

Carotid artery disease Coronary artery disease Diabetes mellitus Hypertension (high blood pressure) Obesity Age Peripheral vascular disease (vascular disease in the extremities, e.g., the legs) Smoking ( Stanley J. Swierzewski, III, M.D. 2007)

Atherosclerosis

It is the most common cause of renal artery stenosis,representing approximately 70

% of cases .( Robbin et al.,1994)

It affects individuals over the age of 55. Approximately 90 % of all renovascular

lesions are secondary to atherosclerosis. The clinical manifestation of atherosclerotic

RAS include hypertension, renal failure (ischemic nephropathy),congestive heart

failure (CHF)and flash pulmonary edema (Safian RD,2001).

Atherosclerosis is a disease involving the elastic arteries(such as the Aorta)and

large and medium sized muscular arteries (as coronary and renal arteies). The basic

lesion is an atheroma, Which consists of a raised focal plaque with alipid core and

covered by fibrous cap within the intima (Robbin et al.,1994)

The pathology of atherosclerosis in details include narrowing of renal artery by

eccentric thickening of the intima by fibrous capped plaque .which consists of

fibrous thickening under the endothelium and adeeper core of amorphous

material .the core is made up of lipid containing macrophage and extra cellular lipid

(sos et al 1983)

Atherosclerotic RAS most often occuirs at the ostium or the proximal 2 cm of Renal

artery. Distal arterial or branch involvement is distinctly uncommon .Renal

revascularization ( Textor sc,2000)

Atheroma increases and advance to cover an entire circumference of an artery

leading to intraluminal narrowing of vessel. Small arteries thus become occluded

leading to ischemic injury to distal organs and tissues Extensive atheromas are often

friable yielding emboli into the distal circulation most commonly noted in the

kidneys (Robbin et al.,1994)

2- Fibromuscular Dysplasia:

Is the second most common cause of renal artery stenosis. It is heterogeneous group

of lesions characterized by fibrous thickening of different layers of arteries. Normal

renal arteries formed of three main layers from inside outwards are tunica intima,

tunica media, and tunica adventitia .Tunica intima is formed of three definite layers:

Endothelium that lies upon thin basal lamina, a subendothelial layer of delicate

collagenous and elastic fibers, and an internal elastic membrane that is prominent

and composed of closely interwoven elastic fibers. Tunica media is formed

exclusively of circulatory disposed smooth muscle cells with small amount of

connective tissue. The adventitia is almost as thick as the media and contains elastic

and collagenous fibers (Lesson et al., 1988).

Different layers of the artery may be involved such as the intima, media and

adventitia thus sub classifying this disease according to the layer affected (Robbins

et al., 1994).

The media type is by far the most common type of the disease. This type of disease

is more common in females and tends to occur in younger age groups, in third and

fourth decades. The lesion may consist of a single well defined constrictions or a

series of narrowing of artery, with the media or distal portion affected .this may be

bilateral or also involved the segmental branches (Robbins et al., 1994)

The fibrous dysplasia is now classified as intimal fibroplasia .Intimal fibroplasias in

addition to stenosis may also cause renal artery dissection or aneurismal formation.

Medial fibroplasia is characterized by presence of multiple micro-aneurysms that

may be associated by large aneurysm.

A concentric segmental stenotic lesion characterizes true Fibromuscular dysplasia.

This may be occasionally associated with A concentric segmental stenotic lesion

characterizes true fibromuscular dysplasia. This may be occasionally associated

with disruption of internal elastic membrane causing dissecting aneurysms the

patient with subadventitial fibroplasia usually present with severely stenotic lesion

characterized by dense collagen deposition in the outer portion of the media (walsh

et al .,1992)

3- Dissecting aortic aneurysm involving ostia of the renal artery:

it is a dissecting hematoma in which blood is present within the wall of the vessel

and spreads or dissect longitudinally thus creating a cavity by separating the tissue

layers .In nearly all instances the dissection is in the media(Andersons ,.1995)

Dissecting aneurysms occur more often in men, aged between 50 and 70 years.

Before the age of 40 there is nearly equal male to female distribution .Half of all

dissection in women occurs before the age of 40 and during pregnancy. Other causes

include Marfan's syndrome, bicuspid aortic valve and coarctation of the

Aorta( Desanctis et al.,1987)

Morphology; the dissecting column of blood is located primarily between the outer

and middle third of aortic media. An intimal tear that continues into the media is

presumed to be the origin of the dissecting hematoma. The dissection commonly

extends proximally and distally from the tear. This may simply end in the media and

adventitia or rupture into adjacent tissue or body cavities or may reenter into the

lumen of the aorta or one of its branches. The dissecting process often involves one

of the main branches of the aorta such as the renal arteries. These may be completely

severed from their origin and originate from the dissected cavity 9false cavity0 or

the diameter of the lumen may be narrowed (Andersons, 1990).

4- Takaysu's arteritis:

Takaysu's described a clinical syndrome characterized by ocular disturbance And

marked weakening of pulses of upper extremities (pulse less disease) which is

related to fibrous thickening of the aortic arch with narrowing or virtual obliteration

of the origin of the great vessels arising from the arch (Robbin's et al, 1994).

Morphology; although Takaysu's arteritis clinically involves the aortic arch, in one

third of cases it also affects the reminder of the aorta and its branches In some

patients it is limited to the descending and abdominal aorta. The gross morphologic

changes comprise irregular thickening of the aortic wall with intimal wrinkling.

Histological the early changes consist of an adventitial mononuclear infiltrate with

perivascular cuffing of the vasa vasorum. Later there may be intense mononuclear

inflammation in the media with Langhan's giant cells and central necrosis ( Hallm

1985).

Pathology atherosclerosis:

The renal artery is narrowed by eccentric thickening of the intima.the typical lesion

is the fibrous capped plaque, which consists of fibrous thickening, under the

endothelium and deeper core of amorphous material the core is made up of lipid

containing macrophage and extra cellular lipid. Hemorrhage may occur imo the core

with further compromise ol` the lumen and the media is usually thinned deep to the

plaque the endothelial. surlace may be intact, but in certain instance its integriyis

lost and thrombosis occurs that may completely the vcssel.(Sos et al l983)

shaped tionuation that causes severe pain. This condition can be Fatal if the artery

bursts. A disease, birth detect, .or injury can cause this condition. lt. is usually

caused by arjtgriioselerosis, ‘a common disorder that causes narrowing of arteries

and reduces circulation. Qiglr ___blr,md_pressure als.o contributes to this _ disease.

(Schrcibet,etal l9S4).

Thrombosis of atherosclerosis:

Cholesterol-containing plaques on the arterial walls characterize atherosclerosis. It is

also associated with activation of platelets, blood coagulation, and increased fibrin

turnover, all of which lead to thrombotic complications. Based on this, the authors

hypothesized that patients with atherosclerosis may be at increased risk

thromboembolism.

Authors say, although their results do not establish that atherosclerosis is the cause

of venous thrombosis, there does appear be a link between the two disorders.

Neuro fibromatosis

Neurofibromatosis is a name given to a group of conditions that have several

characteristics in common. "Neuro" refers to nerves, and "fibromatosis" refers to a

growth that is fiber—like inside. Thus, a common characteristic ol the

neurofibromatosis disorders is the growth of round fibrous lumps along the nerves..

These tumors are rarely cancerous, but can cause problems if` they push on the

nerves or other parts ol` the body or it they are visible on the skin. An autosomal

dominant gene causes all types neurofibromatosis since all genes come in pairs, a

person with neurofibromatosis would

have one gene for neurofibromatosis and one "normal" gene.

Polyarteritis nodosa

Is a disease of unknown cause that affects arteries, the, blood vessels, which carry,

oxygenated blood to organs and tissues. It occurs when certain immune cells attack

the affected arteries-. . The condition affects adults’ more frequently than children.

It damages the tissues supplied by the affected arteries because they don’t receive

enough oxygen and nourishment without a proper blood supply. In this disease,

symptoms result from damage to affected organs, often the skin, heart, kidneys, and

nervous system.

Generalized symptoms include fever, fatigue, weakness, loss of appetite, and

weight loss. Muscle aches (myalgia) and joint aches (arthralgia) are common. The

skin may show rashes, swelling, ulcers, and Lumps (nodular lesions).

Nerve involvement may cause sensory changes with numbness, pain, burning, and

weakness. Central nervous system involvement may cause strokes or seizures.

Kidney involvement can produce varying degrees of renal failure

involvement of the arteries of the heart may cause a heart attack (acute myocardial

infarction), heart failure, and inflammation of the sack around the heart

(periearditis). (Schreiber ,etal 1984l) ‘

Pathophysiology

Pathogenesis of hypertension in RAS Renin cleaves the proenzyme

angiotcnsinogen to form angiotensin l, and, in the ,presence of angiotensin-

converting enzyme (ACE). Is converted to angiotensinll. Angiotensin ll has several

important functions IT elevates blood pressure directly by causing systemic.

Vasoconstriction, (ii) it stimulates. Aldosterone secretion, causing sodium

reabsorption and potassium and hydrogen ion secretion, and (iii) it changes the

intrarenal hemodynamics, such as diminishing glomerular filtration by decreasing,

glomerular capillary surface area and redistributing intrarenal blood flow. The salt

and water retention (caused by excess aldosterone production) is rapidly excreted by

the contralateral (normal) kidney by pressure

natruresis. . Animal models for renovascular hypertension have helped to elucidate

the pathophysiology of hypertension in- patients with RAS. The rennin- angiotensin

—aldosterone system plays an important role (Olin JW, 1996). ln animals, the two

kidney—one clip (2k-1c) models is the classic model for renin—mediated

hypertension and is analogous to unilateral RAS in humans. The one kidney-one clip

(1k—lC) model of renovascular hypertension is a model for volume-mediated

Hypertension and is analogous to bilateral RAS or RAS affecting a solitary

functioning kidney in humans. Although the acute phases of` these models are

similar. different events occur in the chronic phase. In the (2k-1c) model of

(unilateral _ RAS), decreased renal blood flow stimulates the production of

renin (fig)This produces a cycle of rennin—dependant ’ hypertension. in the 1K-1C

model of Renovascular hypertension, there is a similar decrease in blood flow to the

affected kidney, acutely causing the production of rennin and

the synthesis of angiotensin ll and aldosterone (fig) (Olin jW, l996). Angiotensin ll

directly elevates blood pressure and aldosterone causes salt and water retention. ln

this model, there is not a normal kidney that can sense the elevated blood

Pressure, therefore, pressure natruresis does not occur. Increased aldosterone causes

sodium and water retention and volume expansion. The expanded plasma volume

suppresses plasma renin activity, thus converting the animal form renin- mediated

hypertension to volume-mediated hypertension During this stage, administration of

an ( ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) does not decrease

blood pressure or change renal blood flow.

Dietary restriction of sodium or administration of diuretics returns the subject to a

renin—mediated form of hypertension and restores sensitivity to an ACEI or ARB.

Functional renal insufficiency may occur in humans when ACEls are

Administered to patients with bilateral RAS or RAS to a solitary kidney,

especially in the volume-contracted state. (Vaughan JR, 1973)

Pathophysiology of ischemic nephropathy

There are numerous reports suggesting that patients who develop azotemia while

receiving ACE inhibitors have bilateral RAS, RAS to a solitary kidney, or

decompensated CHF in the sodium—depleted state (Textor SC 2000).

There are two mechanisms by which renal functional impairment may occur with

the use of antihypertensive agents. The first may occur with any antihypertensive

agent when a critical perfusion pressure is reached below which the kidney no

longer receives adequate perfusion. This has been shown by the infusion of sodium

nitroprusside in patients with high grade bilateral RAS. When the critical perfusion

pressure was reached, the urine output, renal blood flow, and glomerular filtration

rate declined and later returned to normal when the blood pressure increased above

this critical perfusion pressure. The exact pressure necessary to perfuse a kidney

with RAS. Varies with the degree of stenosis and is different among patients,

(Textor SC 2000).

The second mechanism is confined to patients receiving A ACEI or ARB

agents and may occur despite no significant change in blood pressure. (Textor SC,

1997)

Patients with high—grade bilateral RAS or RAS to a solitary kidney may be highly

dependent on Angiotensin ll for glomerular filtration. This is a particularly common

in-patient who receive A combination of ACEI and diuretic (Watson MI, 1983) or

in -patients who are placed on a sodium—restricted diet. Under these circumstances,

the constrictive effect of `Angiotensin ll on the efferent arteriole allows for the

maintenance of normal transglomerular hydraulic pressure. thus allowing glomerular

filtration to remain in the presence of markedly diminished blood flow. in this

instance glomerular filtration is

Clues to the diagnosis of RAS

A-Hypertension:

Individuals who develop hypertension between the ages of 50 and 55 are most likely

to have primary (essential) hypertension. lf the initial diagnosis of hypertension in

an adult is made before the age of 30, it is usually the result of fibromuscular

dysphasia. Because atherosclerosis occurs in older individuals, it is usually the cause

of RAS after the age of` 55. Accelerated or malignant hypertension has also been

associated with a very high prevalence of RAS Resistant hypertension is defined as

failure to normalize blood pressure

<l40/90 mm Hg after a good medical regimen consisting of at least three drugs with

different mechanisms of action The diagnosis of renovascular disease should be

strongly considered in-patients with resistant (Arch intern med. l997)

B- Physical examination

In general, the physical examination is of limited help although a systolic

abdominal bruit is common and nonspecific, the presence of a systolic/diastolic bruit

especially over the epigastriurn, may point to underlying renal artery disease (Olin

JW, 1999). The presence of a diastolic component to the bruit indicates that the

degree of narrowing of the artery is severe because there is continued flow during

diastole.

C—Renal function

Studies found that 71% of patients with an atrophic kidney 1% ot"

had severe stenosis or complete occlusion of the renal artery ipsilateral to the small

kidney. Studies have shown that if there is a discrepancy in the size between the tow

kidneys or if one kidney is atrophic, there is a 60% chance that the contralateral

renal artery

Renovascular disease in children:

Renovascular disease constitutes between 4.5% and 11.5% of cases of secondary

hypertension in children (fry et al., 1983). The most common abnormality is some

from of renal artery stenosis .this may be an isolated abnormality or may be

associated with idiopathic hypocalcaemia, Marfan's syndrome, rubella syndrome,

Takaysu's disease or neurofibromatosis. Histologically, the commonest lesion is

Fibromuscular Dysplasia which may result in areas of arterial narrowing alternating

with aneurismal dilatation (string of beads) appearance angiographic ally.

Occasionally , intimal proliferation predominates and this is well recognized in

neurofibromatosis (fry . et al.,1983).

INTRODUCTION

Hypertension is a major cause of disability and death throughout

the world. Renal artery stenosis is an etiological factor for a small but

Significant component of this disease with varying estimation of

Prevalence from l%—l0% of patient with hypertension screened (l).

Renal artery stenosis is the narrowing of one or both renal areteis or

their branches that can cause hypertension by intiating the release of the

enzyme renin from juxtaglomerular cells of the affected kidney. The

cross section of the lumen must be decreased by at lest 60%before the

occlusion becomes hemodynamically significant . It is_ the most frequent

cause of curable hypertension but it accounts for less than 2% of all cases

of hypertension (2)

Atherosclerotic renal artery stenosis is the most commen primary

disease of renal arteries and it is associated with two major clinical

syndromes,hypertension and ischemic renal disease(3)

In addition, medical treatment of renovascular hypertension

caused by Renal artery stenosis has been proved to be less effective than

percutaneous or surgical revascularization Therefore, patients suspected

of having RAS should undergo adequate screening(4) -

W ith the increase in prevalence of renal artery stenosis and

ischemic nephropathy clinicians dealing with renovascular disease need

noninvasive diagnostic tools and effective theraputic measures to resolve

the problem successfizlly (5).

Renal artery stenosis most commonly from fibromuscular

dysplasia . However, among patients with _a significant RAS, only two-

thirds show improvement of hypertension after revascularization and

" 27%-80% show improvement or stabilization of renal function. When

left untreated, atheromatous RAS tends to worsen, leading to renal artery

thrombosis (6) I

Color Doppler ultrasound, and Magnetic resonance angiography

(MRA), spiral computed tomography · angiography (CTA), Digital

subtraction angiography (DSA) and Renal seintigraphy can be used in

combination to achieve adequate screening of patients. This article

describes the roles of these modalities in diagnosis of Renal artery

stenosis( RAS) and presents an algorithm for their use. (7)

Color Doppler ultrasound has emerged as areliable method

helping in the diagnostic work-up otpaticnts xx ith suspected renox·ast·ular

disease as renal artery stenosis that causes i·enox·ascular hypertension. (8)

color Doppler has the advantages of being non invasive and

inespeiisne. llou·ex-er. regard to the role. loo approaches are used to

detect l{,»·‘\S with Doppler US; direct visualiyatioii olthc renal arteries and

analysis ol` lIIlI`£ll`L`Ilitl Doppler xxavcliirins (9}

E: `l`he lirst approach involves direct scanning ol the main renal arteries

i` with color or power Doppler US lollowed by analysis ol` renal artery

velocity with spectral Doppler US (lll)

Magnetic resonance angiography (MRA) has amaior role in

j`_ diagnosis ol` renal stenosis ln addition ,in recent study it has been used

to measure the direct pressure in renal artery across the stenotic tract

on

Renal magnetic resonance(MR) angiography allows accurate

evaluation ot` patients suspected to have renal artery stenosis without the

risks associated with nephrotoxic contrast agent,ioni2ing radiation, or

arterial catheterization. Other applications of renal MR angiography are

mapping the vascular anatomy lor planning renal revascularization.

planning repair ol` abdominal aortic aneurysm, assessing renal bypass

gratis and renal transplant anastomosis. and evaluating vascular

involvement by renal tumors(l2).

(_iadolinium~enhanccd MR/\ is now available on high—lield—

. strength imaging systems with high perl"orma1ice gradients which are

. capable ol`pcrt`or1ning breath-hold three-dimensional spoiled gradient--

ccho imaging with short repetition times and echo times (13)

Renal angiography is the undisputed golden standacrd in the

diagnostic work_up lor evaluation ol` rcnovascular disease (14)

Spiral (ZT angiography is able to image large columns oftissue

very rapidly in a2(}-30s breath-hold has led to the development ol` Cl`

angiography. This produces higher quality axial images with better

W contrast enhancement. than conventional Cl` and has the added

_ advantages ol` being able to produce 2].) coronal. sagittal. oblique and

curved planar reconstructed images as well the 3D maximum intensity

projection (MP) and shaded surlace display (SSD) reconstructed

M images. (15).

Color Doppler has the advantages of being noninvasive and inexpensive. However,

regard to the role. Two approaches are used to detect RAS with Doppler US: direct

visualization of the renal arteries and analysis of intrarenal Doppler waveforms(9)

The first approach involves direct scanning of the main renal arteries with color or

power Doppler US followed by analysis of renal artery velocity with spectral

Doppler US(9)

An anterior or anterolateral approach usually allows exploration of both renal

arteries with an adequate angle of insonation. A coronal approach can be used when

bowel gas is present. Owing to various factors such as gas interposition or the

anatomy of the left renal artery, a complete examination of both renal arteries can be

achieved in only 50%–90% of cases(10)

Signal enhancement can be achieved by administering contrast agents that facilitate

visualization of the renal arteries However, the clinical impact of US contrast agents

remains to be determined, and the potential of contrast agents to increase the

maximum Doppler shift remains controversial (11)

Renal angiography is the undisputed golden standaerd in the diagnostic work_up for

evaluation of renovascular disease (8)

Magnetic resonance angiography (MRA) has amajor role in diagnosis of renal

stenosis In addition .,in recent study it has been used to measure the direct pressure

in renal artery across the stenotic tract (12)

As the prevalence of RAS is 20% –30%. In this selected population, the

investigation should be extended to noninvasive studies that will allow detection of

( Renal artery stenosis ) RAS suspected by using several clinical criteria (13)

Gadolinium-enhanced MRA is now available on high-field-strength imaging

systems with high performance gradients, which are capable of performing breath-

hold three-dimensional spoiled gradient-echo imaging with short repetition times

and echo times (14)

The main limitations of MRA are (a) evaluation of branch vessels, (b) the presence

of a metallic stent, (c) detection of accessory arteries, and (d) evaluation of small

renal arteries. Even though evaluation of renal artery branches is not always easy

with MR angiography, detection of fibro muscular dysphasia involving the main

renal artery is sometimes possible (15)

Renal scintigraphy has an important role in diagnosis of renal artery stenosis and.

kidney with renovascular hypertension may exhibit impaired function during

(ACEI ) This phenomenon is observed mainly in patients with bilateral RAS or with

arterial stenosis in a solitary kidney; it is believed to be caused by disruption of the

autoregulation system of the glomerular filtration rate (GFR) (16)

Glomrular filtration rate (GFR) which becomes dependent on angiotensin II under

conditions of low perfusion. Although a decline in the GFR can be induced by ACE

inhibition in the affected kidney of patients with unilateral RAS, the contralateral

kidney preserves the overall renal function In patients with unilateral RAS, a

unilateral change in renal function induced by ACE inhibition can be revealed with

scintigraphy. (17)

ACE inhibitor scintigraphy is performed after intravenous injection of technetium-

99m mercaptoacetyltriglycine (MAG3), iodine-131 orthoiodohippurate (OIH), or

Tc-99m diethylenetriaminepentaacetic acid (DTPA). Sequential images and

scintigraphic curves are obtained for 30 minutes after injection ACE inhibitor

scintigraphy is performed 1 hour after an oral dose of 25 mg of captopril. (18)

In these patients, ACE inhibitor scintigraphy induces significant changes in the

time-activity curves of the affected kidney in comparison with baseline scintigraphy.

Such changes are not observed in patients with nonsignificant RAS or normal renal

arteries. . ACE inhibitor scintigraphy is performed 1 hour after an oral dose of 25

mg of captopril or 15 minutes after an intravenous dose of 0.04 mg/kg of enalapril

maleate. ACE inhibitor therapy should be stopped 2–5 days prior to the study

according to the half-life. (18)